Immunotherapies Take Center Stage at ASCO 2015

By Chase Doyle

Although the idea of immunotherapy is far from new, this exciting treatment modality continues to bring with it new challenges for the healthcare industry. As witnessed at this year’s American Society of Clinical Oncology (ASCO) annual meeting in Chicago, immunotherapy remains a hotly debated topic. As tumor targets keep expanding, immuno-oncology techniques to combat cancer are rapidly evolving, including pathways such as PD-1/PD-L1 inhibition and adaptive cell therapy. Sharon Karlsberg, Lead Principal, Oncology Marketing Solutions, ZS Associates—a global firm focused on improving business performance—acknowledges the enthusiasm for immunotherapies, while at the same time recognizes that many questions remain to be answered:

Will community oncologists be comfortable with the sizeable toxicity risks that come alongside the significant gains in efficacy we see with combination immunotherapy?

Will testing for PD-L1 expression, a biomarker that identifies patients who respond better to anti-PD1/anti-PDL1 therapy, become common clinical practice?

How will providers, patients and the healthcare system adapt to ensure cancer patients have access to these high cost therapies?

In a survey conducted by ZS Associates and M3 Global Research of 93 oncologists attending ASCO, physicians noted that:

“Historically, community prescribers have been less prone to make significant changes in clinical practice until they’ve had more time and experience with new therapies. I expect immunotherapy use in oncology clinical practice will grow significantly in the coming years, especially as new molecules and combination treatments win FDA approval,” said Ms. Karlsberg.

The Promise of Immunotherapy Presented at ASCOAccepting the 2015 David A. Karnofsky Memorial Award and Lecture, Suzanne L. Topalian, MD, Professor, Oncology and Surgery at Johns Hopkins University School of Medicine and the Director of the Melanoma Program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, spoke about anti-PD1 therapy.

“The immune system is in many ways the ‘ideal’ anti-cancer weapon,” said Dr. Topalian. “If we can educate or prime the immune system the right way to recognize cancer, this immunity should last for a lifetime.”

Immune checkpoints, which are molecules expressed on the surface of activated immune cells, can be exploited by cancers in an effort to evade detection. Because these molecules can be turned off to terminate the immune response at the right time—thus avoiding normal tissue damage—they are also susceptible to cancer’s subterfuge.

“Our job as cancer immunotherapists,” said Dr. Topalian, “is to block these checkpoints and therefore turn on immune responses in the right way.”

In the CheckMate057 randomized, phase 3 trial comparing nivolumab to docetaxel, a new standard of care for the treatment of previously-treated non-squamous non-small cell lung cancer (NSCLC) was set. Patients treated with nivolumab had an overall survival of 12.2 months compared with 9.4 months with docetaxel and response rates of 19.2% and 12.4%, respectively (n=582).

Because PD-1/PD-L1 and CTLA-4 represent distinct but complementary pathways involved in the negative regulation of antitumor immunity, there is rationale for combining therapies to boost effectiveness.

In fact, the double-blind CheckMate067 trial validated this hypothesis, showing that immunotherapy combination reduced the risk of death or progression for untreated melanoma by more than half compared with a single agent. Patients (n=945) treated with nivolumab plus ipilimumab had a median progression-free survival (PFS) of 11.5 months compared with 2.9 months for ipilimumab alone and 6.9 months with nivolumab monotherapy. Median PFS with the combination and with nivolumab alone increased to 14 months among patients whose tumors tested positive for PD-L1, the target of nivolumab.

Along With the Promise of Immunotherapy Comes Concerns

In the CheckMate067 trial mentioned earlier, the improvement in PFS also came with the price of increased toxicity. In the combination arm, 55% of patients experienced Grade 3/4 adverse events. These adverse events included diarrhea, elevated liver enzymes, colitis, rash and fatigue.

“As the name in the class implies—checkpoint inhibitors—a natural break on the body’s immune system is being removed,” said Ms. Karlsberg. “Toxicities might be comparatively mild in most monotherapy regimens, but issues arise with combination therapy. When half of patients experiencing Grade 3/4 adverse events are seen, that can be debilitating.”

According to Jeffrey Weber, MD, PhD, Senior Member and Director of the Comprehensive Melanoma Research Center at Moffitt Cancer Center in Tampa, FL, for certain patient subgroups, this risk of toxicity with combination therapy is better than the alternative.

“If you're in a BRAF wild-type population,” said Dr. Weber, “targeted therapy, at least for now, is off the table. So it's the BRAF wild types who have aggressive disease that I think will go on the nivolumab/ipilimumab combination… In addition, my prediction is that someone who is PD-L1 negative would also truly benefit from getting the combination.”

Regarding sequencing of immunotherapies, the ZS-M3 survey revealed a divide among oncologists over their preferred choice of front-line treatment for BRAF-mutated, melanoma patients. While 45% of oncologists strongly agree that BRAF mutation-positive metastatic melanoma patients should be treated first with a combination of BRAF-MEK inhibitors, another 32% of oncologists indicated that they strongly prefer to initiate treatment with immunotherapy to offer the best chance of extending survival.

Costly CombinationsOther than disease itself, perhaps the single biggest challenge facing patients and providers is cost. According to Leonard Saltz, MD, from Memorial Sloan Kettering Cancer Center, New York City, nivolumab costs $28.78 per mg of drug, whereas ipilimumab costs $157.46 per mg.

“To put that into perspective,” said Dr. Saltz, “that’s approximately 4000 times the cost of gold.”

With doses ranging anywhere from 2mg/kg to 10mg/kg, these figures add up quickly. In the melanoma combination trial, for example, the cost of using ipilimumab alone was $158,282 (for a median PFS of 2.9 months), the cost of nivolumab alone was $103,220 (for a PFS of 6.9 months), and the cost of the combination was $295,566 (for PFS of 11.4 months).

Alas, checkpoint inhibitors are not checkbook inhibitors. “There's only a finite amount of money we can devote to healthcare,” said Dr. Weber. “But I think the companies are very aware of this, and a lot of them are thinking about innovative models to limit costs, ranging from only requiring payment if the drug works to charging a certain amount of money for a drug and [offering] subsequent treatments [for] free.”

Mismatch Repair in Colorectal Cancer as an Indicator of Response to Immunotherapy

One of the most significant trials presented at ASCO may have come in a cancer typically unresponsive to PD-1/PD-L1 blockade.

“I think the most impactful [study] was the response rate to pembrolizumab in MSI-high colorectal cancer patients, which supports this idea that if you have lots of mutations in your tumor, it increases the likelihood that you might be responsive to immunotherapy,” said Dr. Weber.

In this trial presented, pembrolizumab was used to treat three cohorts: colorectal cancer patients with normal mismatch repair (MMR) mechanisms (n=25), colorectal patients with deficient MMR (n=13), and patients with other MMR-deficient cancers (n=10). The difference in the response rates was staggering: 0% of patients with MMR-proficient colorectal cancer responded to pembrolizumab vs. 62% of patients with MMR-deficient tumors.

For Dr. Weber, who was interviewed by Sharon Karlsberg, these data have far-reaching implications, not only for colorectal cancer but also for predicting responses to anti-PD1 in many other cancers. Patients with gastrointestinal, gynecologic, and prostate cancer also showed a 60% response rate to pembrolizumab, with improved overall survival, if they were MSI-high.

Is the PD-L1 Biomarker Ready for Prime Time?

The ZS-M3 survey also revealed that a consensus has yet to be reached regarding the use of PD-L1 testing in all patients. For NSCLC and metastatic melanoma patients, the majority of oncologists surveyed (54%) said they would treat “all comers” regardless of PD-L1 expression and potentially different responses to anti-PD1/ anti-PDL1 therapy. For metastatic bladder cancer patients, however, only 38% of oncologists answered the same, suggesting that PD-L1 expression may confer treatment-altering information.

“Clearly, the oncology community is actively debating these issues,” noted Ms. Karlsberg. “KOLs are strong advocates for what they believe is the most groundbreaking treatment on the basis of recently released clinical data, but community prescribers are not making that shift so quickly. Oncologists are divided on whether they should start with targeted agents or immunotherapy, and they are divided on whether they should be testing patients for PD-L1 status and treating on the basis of that biomarker.”

CAR-T Cells: The Best Is Yet To Come
Despite its day in the sun, PD-1/PD-L1 inhibitors are not the be-all, end-all of immunotherapy. There are at least a dozen other checkpoint inhibitor targets waiting to be explored, not to mention different mechanisms of action altogether.

One such mechanism, chimeric antigen receptor (CAR) T cells, is already showing great clinical promise in patients with hematologic malignancies. CAR-T cells are engineered receptors used to graft the specificity of a monoclonal antibody onto a T cell. These T cells are then re-infused into the patient with the potential benefit of recognizing and killing cancer cells.

Although still in its relative infancy, the field is moving fast. According to Madhav Dhodapkar, MD, Professor of Medicine and Immunobiology and Chief, Section of Hematology at Yale University, however, if CARs are to progress beyond limited centers, the safety and efficacy of these agents must improve.

“We need to better understand the biology of cytokine release syndrome and neurotoxicity,” he said, “and we must have better predictors and biomarkers.”

Despite these obstacles, Dr. Weber is confident that CARs will ultimately thrive.

There is Still Much to Talk About

As ASCO ended, it was clear that presentations of immunotherapy clinical data provided a thought-provoking forum for discussion, both optimistic and cautious. It also became clear that we are only just beginning to understand the power of this unique new tool in the anti-cancer armamentarium. As Ms. Karlsberg pointed out, “It’s exciting to see immunotherapies playing such a prominent role at ASCO. It’s especially exciting to witness physician enthusiasm and discussion about the new clinical data. It feels like we’re on the frontier of a truly meaningful win for patients.”

About the Contributors

ZS is the world’s largest firm focused exclusively on improving business performance through sales and marketing solutions, from customer insights and strategy to analytics, operations and technology. More than 3,000 ZS professionals in 21 offices worldwide draw on deep industry and domain expertise to deliver impact where it matters for clients across multiple industries. To learn more, visit www.zsassociates.com or follow us on Twitter (@ZSAssociates) and LinkedIn.

M3 Global Research provides the most comprehensive and highest quality market research recruitment and support services available to the global healthcare industry with relationships with over 2.5 million physicians in more than 70 countries worldwide. M3 Global Research operates an ISO 26362 certified panel with the highest quality data collection and project management capabilities that cover the spectrum of quantitative and qualitative techniques utilized today. In addition to market research, M3 Global Research provides valued services to today’s medical professionals that include medical education, ethical drug promotion, clinical development, job recruitment, and clinic appointment services. M3 has offices in Tokyo, Washington D.C., Fort Washington, PA, Rochester, NY, San Mateo, CA, Oxford, London, and Seoul.